Phosphorylation of Pal2 by the protein kinases Kin1 and Kin2 modulates mRNA splicing in the unfolded protein response in yeast.

During cellular stress in the budding yeast , an endoplasmic reticulum (ER)-resident dual kinase and RNase Ire1 splices an intron from mRNA in the cytosol, thereby releasing its translational block. Hac1 protein then activates an adaptive cellular stress response called the unfolded protein response (UPR) that maintains ER homeostasis. The polarity-inducing protein kinases Kin1 and Kin2 contribute to mRNA processing.

Metabolic Rewiring in Response to Biguanides Is Mediated by mROS/HIF-1a in Malignant Lymphocytes.

Metabolic flexibility allows cells to adapt to various environments and limits the efficacy of metabolic drugs. Therapeutic targeting of cancer metabolism relies on defining limiting requirements and vulnerabilities in the highly dynamic metabolic network. Here, we characterize the metabolic reprogramming and identify cancer-specific metabolic vulnerabilities in response to the pharmacological inhibition of mitochondrial complex I.

A novel role for protein kinase Kin2 in regulating HAC1 mRNA translocation, splicing, and translation.

A signaling network called the unfolded protein response (UPR) resolves the protein-folding defects in the endoplasmic reticulum (ER) from yeasts to humans. In the yeast Saccharomyces cerevisiae, the UPR activation involves (i) aggregation of the ER-resident kinase/RNase Ire1 to form an Ire1 focus, (ii) targeting HAC1 pre-mRNA toward the Ire1 focus that cleaves out an inhibitory intron from the mRNA, and (iii) translation of Hac1 protein from the spliced mRNA. Targeting HAC1 mRNA to the Ire1 focus requires a cis-acting bipartite element (3'BE) located at the 3' untranslated leader.

Activation of protein kinase PKR requires dimerization-induced cis-phosphorylation within the activation loop.

Protein kinase R (PKR) functions in a plethora of cellular processes, including viral and cellular stress responses, by phosphorylating the translation initiation factor eIF2α. The minimum requirements for PKR function are homodimerization of its kinase and RNA-binding domains, and autophosphorylation at the residue Thr-446 in a flexible loop called the activation loop. We investigated the interdependence between dimerization and Thr-446 autophosphorylation using the yeast Saccharomyces cerevisiae model system.

An ire1-phk1 chimera reveals a dispensable role of autokinase activity in endoplasmic reticulum stress response.

The endoplasmic reticulum transmembrane receptor Ire1 senses over-accumulation of unfolded proteins in the endoplasmic reticulum and initiates the unfolded protein response (UPR). The cytoplasmic portion of Ire1 has a protein kinase domain (KD) and a kinase extension nuclease (KEN) domain that cleaves an mRNA for encoding the Hac1 transcription factor needed to express UPR genes. During this UPR signaling, Ire1 proteins self-assemble into an oligomer of dimers, which essentially requires autophosphorylation of a constituent activation loop in the KD.

Novel proteasome-inhibitory syrbactin analogs inducing endoplasmic reticulum stress and apoptosis in hematological tumor cell lines.

The proteasome has been recognized as a druggable target in cancer cells, and this has led to searches for pharmacologic agents that target this cellular organelle for cancer therapeutic purposes. Syrbactins are a group of microbial metabolites consisting of two related families, the glidobactins and the syringolins. Some members of this group have revealed cytotoxic efficacy in tumor cells, and more recently it was discovered that they exert proteasome-inhibitory function.